Pd-Catalyzed C(sp~3)-H Functionalizations And Interannular Meta-C-H Arylation Based On Directing Strategy

Transition-metal-catalyzed C-H functionalization has emerged as an efficient and atom economic method for preparing natural compounds and pharmaceutical targets. However, selective functionalization of aliphatic C(sp~3)-H bonds, especially unactivated methylene C(sp~3)-H bonds, presents a practical challenge due to the robust nature of such bonds. In addition, controlling the positional selectivity of C-H cleavage in aromatic compounds that contain multiple C-H bonds is an outstanding challenge that must be addressed. This dissertation is mainly focused on palladium-catalyzed unactivated C(sp~3)-H bonds functionalization and interannular meta-selective C-H bonds arylation, which includes:1. Palladium-Catalyzed Sequential Monoarylation/Amidation of ?-Methyl C(sp~3)-H Bonds of Alanine for Synthesis of a-Amino-?-LactamsA palladium-catalyzed sequential monoarylation/amidation of alanine ?-methyl C(sp~3)-H bonds using a easily removable 5-methoxyquinolin-8-amine auxiliary is described. This process is highly efficient and compatible with a variety of functional groups, providing a general and practical synthetic protocol for the synthesis of various ?-amino-?-lactams. The synthetic potential of this protocol is applied to the synthesis of orthogonally protected trans-?,?-diamine.2. Palladium-Catalyzed Arylation of Unactivated y-Methylene C(sp~3)-H and ?-C-H BondsA palladium-catalyzed arylation of unactivated y-methylene C(sp~3)-H and remote ?-C-H bonds using a bidentate oxazoline-carboxylate directing group has been developed. A preliminary study on diastereoselective arylation of y-methylene C(sp~3)-H bonds is conducted by using a chiral oxazoline-carboxylate directing group.3. Palladium-Catalyzed Interannular meta-C-H ArylationThe interannular meta-selective C-H arylation of biaryl-2-trifluoroacetamides using Pd(?)/norbornene catalysis is reported. The installation of trifluoroacetyl protecting group to tune the electronic property and binding ability is essential for the interannular selectivity. A dimeric palladacyle, comprising two cyclopalladated trifluoroacetamino biaryl units linked through trifluoroacetamide, was isolated and confirmed to be the key intermediate. Furthermore, the resulting products could be further elaborated via ipso-alkynylation and/or directed ortho-C-H functionalization, allowing access to various fully functionalized biaryl-2-amine derivatives.